tbuckley/cabot-search huggingface dataset:
Abstract 14919: EN-RAGE is Associated With Improved Outcomes in Hospitalized COVID-19 Patients
Authors: Javaria Ahmad, Juan Solorzano, Keerthish Jaisingh, Sindhu Thevuthasan, Addison Foster, Megan Watts, Wayne W Orr, Chris Kevil, Gopi Krishna Kolluru, Paari Dominic
Journal: Circulation (2022)

Background: Inflammation has been implicated in the pathogenesis, severity, and outcomes of COVID-19. Extracellular newly identified receptor for advanced glycation end-product (EN-RAGE), a soluble EF-hand calcium-binding protein, causes integrin activation, activates inflammation, and upregulates the synthesis of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1. While it is positively associated with atherosclerosis, high EN-RAGE levels have been shown to predict remission of auto-immune diseases. The role of EN-RAGE as a biomarker in COVID-19 is unknown. Methods: Serum EN-RAGE levels were measured from blood samples of 146 COVID-19 in-patients using Myriad® Cytokine MAP and compared between the subgroups based on race and outcomes. T-test, Chi-square, and multivariable regression analysis were performed to identify the correlation of EN-RAGE with race and outcomes. Results: Of 146 patients (mean age=59 years), 60% were female, 35% were White, and 60% were African Americans. 21 of the 146 (14%) patients died. Mortality was higher in Whites compared to African Americans (21% vs 10%) consistent with CDC data showing higher mortality in Whites compared to non-Whites. Surprisingly, African Americans had significantly higher EN-RAGE levels compared to Whites. (574.6 vs 360.9 respectively, p=0.002). Congruently, EN-RAGE levels were significantly higher in the patients who survived compared to the patients who died. (514.82 vs 336.29, p=0.039) suggesting that increased serum EN-RAGE levels may be associated with improved outcomes in hospitalized COVID-19 patients. Conclusion: Our study reveals a negative association of EN-RAGE levels with in-patient mortality associated with COVID-19 and could possibly be used as a biomarker of survival in hospitalized COVID-19 patients. EN-RAGE levels could partly explain mortality differences based on race. Further studies are required to confirm this association.
Abstract 15005: Tlr4/py14-Caveolin-1-Mediated Endothelial C-iap2 Expression During Schistosomiasis-Associated Pulmonary Arterial Hypertension
Authors: Elizabeth S Villarreal, Ejehi Erewele, Maricela Castellon, Andrew Schwartz, David L Williams, Nicholas W Morrell, Marcelo G Bonini, Claudia L Silva, Sarah E. Lutz, Serpil Erzurum, Richard D Minshall, Suellen D Oliveira
Journal: Circulation (2022)

Introduction: During schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH), hyperproliferation of abnormal endothelial cells (ECs) contributes to development of severe vascular lesions within the lungs; a life-threatening phenomenon that remains with no target therapy. Hypothesis: Here, we found that antigenic molecules from the major etiological agent of Sch-PAH, i.e., S. mansoni , amplify the secretion of the antiapoptotic protein c-IAP2 via TLR4-pY14Cav-1 signaling pathway, which we hypothesized to contribute to generation of an EC memory of survival and severity of PAH. Methods/Results: Cav-1 deficiency via shedding of extracellular vesicles (EVs) leads to survival of an apoptosis-resistant EC phenotype during idiopathic PAH. Similarly, S. mansoni egg antigens also reduced lung EC-Cav-1 expression, suggesting that Cav-1 also plays a role during pathogen-associated PAH. Cav-1 depletion via EVs precedes its phosphorylation at residue Tyr14 (pY14Cav-1), which in turn, contributes to EV loading. Among apoptotic regulators, IAPs have been found as a cargo of EVs in different conditions, including in TLR4-activated cells. Accordingly, our data indicates that S. mansoni egg antigen p40 also activated TLR4/NFkB-mediated signaling, inducing c-IAP2 expression and a time-dependent phosphorylation of Cav-1 in human lung microvascular EC (HMVEC-L: 228.2 +/- 38.28% of control; p&lt;0.05; n=4). Moreover, although Sm-p40 alone was unable to induce shedding of EVs, combination with NFkB-associated proinflammatory mediators (TNF-α, IL-6, and ATP), significantly increased EV shedding by HMVEC-L, suggesting that S. mansoni may epigenetically prime ECs, but co-factors are required to induce EV shedding. Finally, Sch-PAH model using EC- Cav1 -/- mice ( End-scl.Cre ERT2 ;Rosa mt/mg ;Cav1 fl/fl ) revealed that Cav-1 absence led to accumulation of eggs within the lungs and loss of eGFP+ cells, indicating that EC-Cav-1 phosphorylation may be required to development of Sch-PAH. Conclusions: Our data suggest that S. mansoni -induced pY14Cav-1 is associated to expression of the anti-apoptotic c-IAP2 protein, which may be critical for prolonged survival of a pathogenic EC phenotype during the development of Sch-PAH.
Abstract 14765: Cardiovascular Safety Reporting Among Cancer Pharmacotherapy Agents in Breast Cancer Clinical Trials
Authors: Arsalan Hamid, Samuel C Thigpen, Javed Butler, Michael E Hall
Journal: Circulation (2022)

Introduction: Cancer pharmacotherapy has been associated with cardiovascular (CV) harm in early phase trials. Later phase (2 &amp; 3) trials offer potential to uncover the frequency of CV harm not identified in smaller early phase trials. We assessed whether the cancer pharmacotherapy agent administered impacts how later phase breast cancer clinical trials exclude patients and report CV safety assessments. Methods: We searched Embase and Medline records for phase 2 &amp; 3 breast cancer pharmacotherapy trials (2018-2019). We examined exclusion criteria due to CV conditions and CV safety assessment through CV imaging, electrocardiograms, or biomarkers. Fischer’s exact test was utilized to compare reporting. Results: After our search, 50 clinical trials were included. Trials administering microtubule inhibitors were most likely to exclude participants with CV conditions (e.g. myocardial infarctions and arrhythmias) compared to other agents (kinase inhibitors etc.) (93.5 vs 68.4%, p=0.04). Trials administering HER-2 receptor antibody agents more often excluded patients with heart failure (HF) or low ejection fraction (EF) compared to other agents (100.0 vs 62.9%, p&lt;0.01). Trials administering anthracyclines frequently exclude patients with HF or low EF, albeit not statistically more than other agents (92.9 vs 66.7%, p=0.07). Only 46% trials performed electrocardiograms, 40% performed CV imaging, and none reported biomarker collection. Trials administering HER-2 receptor antibody agents conducted the greatest CV imaging (p&lt;0.01). While trials utilizing other agents did not selectively perform relevant safety assessments to identify toxicity the agent would be at risk of inducing compared to all agents. Conclusion: HER-2 receptor antibody trials selectively exclude patients with at risk conditions and conduct imaging to monitor cardiotoxicity. However, breast cancer trials using other pharmacotherapies do not have a uniform approach to CV exclusion criteria or safety assessments. Breast cancer pharmacotherapy trials should establish a standardized approach to conduct safety assessments that can identify early CV toxicity specific to the agent administered. This may allow inclusion of high risk patients and generate more generalizable data.
Abstract 14892: Interaction of β <sub>IV</sub> -Spectrin/STAT3 is Responsible for Orienting Concentric versus Eccentric Cardiomyocyte Hypertrophy
Authors: Drew Nassal, Shivangi Mohta, Nehal Patel, Xianyao xu, Mei Han, Peter J Mohler, Thomas J Hund
Journal: Circulation (2022)

Cardiac hypertrophy is critical in the development of heart failure following chronic cardiac stress. In pressure overload, hypertrophy is divided by early adaptive remodeling defined by concentric growth, while chronic hypertrophy associates with eccentric growth and loss in cardiac output. The mechanisms regulating this transition and the impact each profile has in influencing heart function are largely unknown. Previous work identified a role for the structural protein βIV-spectrin and its interaction with the transcription factor, STAT3, in coordinating hypertrophic profiles. Specifically, mice expressing truncated βIV-spectrin lacking interaction with the hypertrophic signaling molecule CaMKII (qv 3J mice) were resistant to βIV-spectrin degradation and maintained concentric hypertrophy and ejection fraction (EF) compared to WT following 6 weeks transaortic constriction (TAC). Alternatively, mutant βIV-spectrin mice (qv 4J ) lacking the STAT3/βIV-spectrin binding domain lead to cytosolic redistribution of STAT3 and associated with reduced EF and LV dilation consistent in eccentric remodeling, suggesting STAT3/βIV-spectrin is a key regulator of hypertrophic profiles and function. This relationship was further examined by adenoviral overexpression of the hypertrophic driver, MEK1/2, on isolated myocytes. As expected, MEK increased the width of WT myocytes, while qv 4J myocytes increased in length. However, application of STAT3 inhibitor S3I-201 on qv 4J myocytes reoriented these cells to growth in width. Additionally, in vivo application of S3I-201 to qv 4J mice was able to restore LV wall thickness and EF over 2 weeks, reinforcing STAT3 as a determinant of hypertrophic profiles. Evaluation of cardiac gene expression profiles from these backgrounds identified consistent elevations in microtubule subunits associated with eccentric growth patterns. Indeed, microtubule growth assays revealed qv 4J myocytes to express significantly enhanced microtubule stability which could be reversed through S3I-201 STAT3 inhibition. Together, these data identify a novel role for βIV-spectrin/STAT3 and microtubule stability in tuning specific hypertrophic profiles and cardiac function.
Abstract 15082: Altered Functional Brain Circuitry in Fetuses With Complex Congenital Heart Disease
Authors: Josepheen D Cruz, Kushal Kapse, Catherine Lopez, Gilbert Vezina, Mary T Donofrio, David L Wessel, Adre du Plessis, Catherine Limperopoulos
Journal: Circulation (2022)

Recent reports describing regional alterations involving critical hubs of the developing brain have emerged in neonates with complex CHD prior to surgery. However, the extent to which postnatal brain connectivity disturbances reflect a prenatal onset of aberrant functional circuitry development is unknown. Here, we investigated whether neural connectivity changes are present in fetuses with CHD before birth. We acquired 176 resting state scans from 156 pregnant women who were prospectively enrolled. We analyzed 76 scans from 61 CHD fetuses (mean±sd:33.4±3.1 gestational weeks, GW); which included transposition of the great arteries, n=22; hypoplastic left heart syndrome, n=20; other CHD, n=34) and 103 scans from 95 healthy controls (33.8±3.3 GW). First, we defined 98 anatomic regions ( nodes ) using a fetal atlas. Next, for each fetus, we computed connectivity – the pairwise Fisher- z transformed Pearson correlation, ( z(r) ) – across all 98 nodes. Only the strongest 4% of connections, or 190 edges , were included. Next, we grouped nodes into 16 clusters, or modules , based on a node’s connectivity to other nodes. We then compared (1) the number of connections within ( w-edges ) and between ( b-edges ) modules, and (2) the strength of connectivity within ( w-strength ) and between ( b-strength ) modules. We expected 12/190 w-edges and 177/190 b-edges but observed 55 and 54 w-edges in healthy (H) and CHD fetuses, respectively, 4.5x greater than the expected. Thus, in both cohorts, the normalized w-edges were significantly greater than the normalized b-edges ( p &lt; 0.001); there were no significant between-group differences. However, w-strength (H,1.16±0.26; CHD, 1.14±0.31) and b-strength (H, 1.05±0.19; CHD, 1.04±0.26) were significantly reduced in CHD ( p &lt;0.001). In both, w-strength was greater than b-strength (p&lt;0.001). For the first time, we demonstrated that CHD functional networks follow normative trajectories where within-module connectivity predominates, both in strength and number, in-utero. Fetal CHD connectivity strength, however, was weaker compared to controls suggesting that altered functional brain circuitry in CHD has its origins in-utero. Further studies are needed to assess the surveillance and prognostic potential of these findings.
Abstract 14908: Vascular Events Associated With Cisplatin Based Combination Therapy: An Analysis From Faers Database
Authors: Chitsimann Mann, Brijesh Patel, midhun malla, Mohammad Almubarak, Wei Fang
Journal: Circulation (2022)

Introduction:Cisplatin is an alkylating agent that has been used to treat various cancer types in combination with other antineoplastic agents. It has been associated with vascular toxicity. However, data is lacking whether one combination is associated with increased risk of vascular events. Methods: We queried 2016-2020 FDA Adverse Reporting System (FAERS) database to analyze the association. We identified cases with the following four combinations: (1) cisplatin + etoposide, (2) cisplatin + gemcitabine, (3) Cisplatin + docetaxel/paclitaxel, and (4) cisplatin + 5-fluorouracil/capecitabine. The effect size is reported as Rate of Reporting (ROR) with 95% confidence intervals (CI). We aggregated various vascular events including pulmonary, coronary, cerebrovascular and peripheral vascular events including venous events. A lower limit of 95% CI &gt; 1 suggests the drug is potentially associated with the event. Results: From 2016 to 2020, we identified 23513 cases of cisplatin combinations. More than 67% of cases had age over 50 years and 47%, 32.9% and 19.9% were males, females and gender not reported respectively. Most cases were reported from the United States (20%). The ROR (95% CI) for Cisplatin + etoposide was 1.55 (1.37-1.75), cisplatin + gemcitabine was 3.40 (3.03-3.82), cisplatin + docetaxel/paclitaxel was 1.10 (0.90-1.37), and cisplatin + 5FU/capecitabine was 2.34 (1.88-2.92). More than 25% had either a life-threatening condition or died. Conclusion: Cisplatin with Gemcitabine is associated the highest ROR amongst the studied Cisplatin -chemotherapy based combinations. The results obtained from the study emphasizes the role of multi-disciplinary care including cardio-oncology in order to minimize and effectively manage the vascular toxicity.
Abstract 14749: Assessment for Neurocognitive Change After Catheter Ablation for Atrial Fibrillation
Authors: Kevin Clark, Richard S Amara, Jasmine Singh, Keneil Shah, Muhammad Haq, Calvin Kagan, Stephen Shorofsky, Jeff Rottman, Vincent Y See, Timm Dickfeld
Journal: Circulation (2022)

Introduction: Several studies have been conducted to evaluate the neurocognitive effects of catheter ablation for atrial fibrillation. However, these studies have found mixed results. Theoretically, silent peri-procedural stroke might yield a worsening of neurocognitive function, though normalization of heart rhythms might yield improvement. The purpose of this study was to prospectively follow patients after catheter-ablation for paroxysmal or persistent atrial fibrillation with serial telephone-based Montreal Cognitive Assessments (t-MoCA) over 6 months to evaluate for changes in neurocognitive function. Hypothesis: No change in t-MoCA scores between baseline and 1-month, 3-months, and 6-months after catheter ablation for atrial fibrillation. Methods: All consenting patients who underwent first time or redo catheter ablation for atrial fibrillation (with either radiofrequency- or cryo-ablation) between January 2021 and May 2022 were enrolled in the study. A t-MoCA was conducted to measure cognitive function at baseline, 1 month, 3 months, and 6 months from the date of catheter ablation. Only patients who completed at least 1 month of follow-up were included for analysis. Paired t-tests and one-way ANOVA were used to assess for significant differences in t-MoCA scores. Results: 42 patients met criteria for analysis. Paired two-tailed t-test values at 1-month, 3-months, and 6-months demonstrated an increase in t-MoCA score by 2.17 (n=42, p = 0.036), 3.08 (n=27, p = 0.005), and 3.06 (n=24, p = 0.006) respectively when compared to baseline. One-way ANOVA testing showed no significant differences between the 1-month, 3-month, and 6-month scores (p = 0.73). Conclusions: Patients undergoing first time or redo catheter ablation for atrial fibrillation had significant improvement in t-MoCA scores at 1-month, 3-months, and 6-months post-ablation. The improvement seen at 1-month was sustained throughout the 6-months of follow-up. Further long-term assessment is needed to determine if this effect persists over a longer period of time and to potentially correlate these findings with post-ablation atrial fibrillation recurrence.
Abstract 14922: Combined Lineage Tracing and Scrna-Seq Reveals Unexpected First Heart Field Predominance of Human Ipsc Differentiation
Authors: Francisco X Galdos, Carissa Lee, Soah Lee, William R Goodyer, Sharon Paige, Gabriela V Escobar, Adrija Darsha, Aimee Beck, Sidra Xu, Rasmus O Bak, Matthew Porteus, Sean M Wu
Journal: Circulation (2022)

Introduction: During mammalian development, the left and right ventricles arise from early populations of cardiac progenitors known as the first and second heart fields, respectively. While these populations have been studied in non-human model systems, human induced pluripotent stem cells (hiPSCs) present an exciting alternative for modeling early human embryogenesis. A major question is whether hiPSCs can model cardiac progenitor development as seen in animal systems. Hypothesis: Dual TBX5/MYL2 lineage tracing and time course single cell RNA sequencing can uncover the identity of human cardiac progenitor lineage in vitro. Methods: Using CRISPR/Cas9 genome editing we introduced a TBX5/MYL2 fluorescent reporter lineage tracing system into two independent hiPSC lines to identify FHF-progenitors and their descendants. Using a standard biphasic WNT modulation protocol, we differentiated hiPSCs into cardiomyocytes and characterized the expression of TBX5-lineage positive and MYL2 cardiomyocytes between day 3 and day 30 of differentiation. To further characterize the cell populations, present during differentiation, we conducted single cell RNA sequencing on differentiating hiPSCs across 12 timepoints with oligonucleotide-based sample multiplexing. Results: Our reporter system revealed the surprising finding that using a standard WNT modulation small molecule protocol across two cell lines yielded 93.2%±0.80% and 92.1%± 1.60% TBX5-lineage positive cardiomyocytes, respectively. Among MYL2 expressing ventricular cardiomyocytes, we observed 99.0%±0.21% and 93.2±0.84% as TBX5-lineage positive, respectively. ScRNA-seq analysis and trajectory inference revealed high expression of known FHF gene markers relative to murine developmental data and identified a clear bifurcation of cardiac progenitor populations into myocardial and epicardial lineage consistent with a FHF differentiation trajectory. Lastly, a comparison of our data with scRNA-seq data from a recently published 3D protocol reveals the identity of a SHF progenitor population within a 3D system. Conclusions: Our work provides a powerful new genetic lineage tracing approach, as well as a single cell transcriptomic atlas of hiPSCs undergoing cardiac differentiation.
Abstract 15000: Advanced Hemodynamics in the Assessment of Waitlist Mortality
Authors: Alejandro Plana, Mark N Belkin, Nikhil Gupta, Maria Poonawalla, Mikail Siddiki, William Parker, Sean Pinney, Jonathan Grinstein
Journal: Circulation (2022)

Introduction: Our analysis seeks to determine whether it or advanced hemodynamic variables, including aortic pulsatility index (API), pulmonary artery pulsatility index (PAPI), left ventricular stroke work index (LVSWI), or right ventricular stroke work index (RVSWI), correlated more strongly than traditional metrics with waitlist mortality for heart transplant. Hypothesis: Advanced hemodynamic markers of cardiac function, including API and PAPI, correlate more strongly with waitlist mortality than traditional hemodynamic criteria, including SBP and PCWP. Methods: This retrospective analysis of the Scientific Registry of Transplant Candidates (SRTR) included adults listed at all Statuses after the new heart allocation system in 2018. Hemodynamic data was obtained for patients listed after the 2018 policy change. Kaplan-Meier survival analysis was completed, with API, PAPI, LVSWI, and RVSWI as the independent variable stratified into quintiles. Results: There were 9,418 patients listed for heart transplant since the new policy implementation, with 8,636 patients with complete hemodynamic data at listing. Kaplan-Meier survival analysis revealed that API and LVSWI were best at stratifying patients appropriately in terms of waitlist survival with homogeneity of dispersion between groups (Figure 1), (lowest API quintile to highest: HR 2.04, 95%CI 1.94 - 2.15; HR 1.70, 1.59 - 1.81; HR 1.40, 1.29-1.51; HR 1.19, 1.08 - 1.30). The traditional parameters of PCWP, CO and systolic blood pressure had considerable dispersion of risk between quintiles while the right-sided parameters of PAPI and RVSWI did not. Conclusions: Advanced left-sided hemodynamic parameters better risk strategy waitlist mortality and the urgent need for heart transplantation than traditional metrics or right-sided advanced parameters.
Abstract 14826: Single Day Intravenous Sotalol as a Loading Dose to Initiate Oral Sotalol Therapy: Is it Safe and Efficacious?
Authors: Adnan Ahmed, Jalaj Garg, Donita Atkins, Peter Park, Naga Venkata K Pothineni, Scott Koerber, Rangarao V Tummala, Sudharani Bommana, Rakesh Gopinathannair, Andrea Natale, Dhanunjaya Lakkireddy
Journal: Circulation (2022)

Introduction: Due to pro-arrhythmic effects associated with Sotalol, inpatient initiation with QTc monitoring for five doses is recommended. An IV loading dose followed by two oral doses has been shown to achieve steady-state concentrations. Hypothesis: To evaluate the safety of single day loading of IV sotalol in patients with atrial fibrillation and atrial flutter (AF/AFL). Methods: We prospectively evaluated 40 patients at our institution who received IV sotalol as single day loading dose for initiation of oral sotalol therapy for AF/AFL. IV sotalol dose was calculated based on target oral dose as indicated by baseline QTc interval and renal function. Patients' QTc (in sinus) was measured via ECG on 15 minutes intervals and after IV loading completion. Loading was considered complete after second oral dose. All patients were monitored via a mobile cardiac outpatient monitor for 3 days followed by a final 12 ECG. Results: A total of 40 patients were included in the study. The mean age was 69 + 8.2 years, 78.9% of patients were men. QTc significantly increased from 435.9 + 26.4 to 462.9 + 31.6 with following IV loading (p&lt;0.001), that stabilized following oral loading completion (450.63 + 44.4; p=0.12). There were no cases of severe bradycardia, sinus node dysfunction, ventricular arrhythmias. reported. Conclusions: Our study sheds evidence that rapid IV sotalol loading in AF/AFL is safe and efficacious. This will not only provide patient convenience but will lead to reduced economic burden on patients and health care systems.